WWW.DISSERTATION.XLIBX.INFO
FREE ELECTRONIC LIBRARY - Dissertations, online materials
 
<< HOME
CONTACTS



«Topic Thalidomide: A Controversial Chiral Drug Subtopics 1. Why is drug chirality important? 2. What caused the thalidomide tragedy? 3. Why has ...»

Teaching Chemistry Through The Jigsaw Strategy

Example 1

Topic

Thalidomide: A Controversial Chiral Drug

Subtopics

1. Why is drug chirality important?

2. What caused the thalidomide tragedy?

3. Why has thalidomide been approved for sale again?

Level

Secondary 6-7

Curriculum Links

Stereoisomerism

Enantiomerism

Chiral carbon compounds

Medium of instruction

English

Copyright © 2007 by Quality Education Fund, Hong Kong

All rights reserved. Prepared by Professor Derek Cheung, The Department of Curriculum and Instruction, The Chinese University of Hong Kong. No part of this document may be reproduced in any manner whatsoever without written permission, except in the case of use as instructional material in a school by a teacher.

1

1. Why is drug chirality important?

Enantiomers are optical isomers which are nonsuperimposable mirror-image structures. The property of nonsuperimposability is called chirality. A molecule is chiral if and only if it is not superimposable on its mirror image. The most common chiral centre is carbon. When four nonidentical atoms or groups are attached to a tetravalent carbon, the tetrahedral arrangement of the bonds in space results in two enantiomers. Enantiomers can be distinguished by experiments because they have different ability to rotate a beam of plane-polarized light: to the clockwise direction as a dextrorotatory (+)-enantiomer and to the counterclockwise direction as a levorotatory (-)-enantiomer. A mixture of equal portions (50/50) of the (+) and (-) enantiomers is called a racemic mixture.

In 1957, a pharmaceutical company in West Germany introduced a new drug to the market. It was called thalidomide with molecular formula C13H10N2O4. The drug was sold in 46 countries under at least 37 brand names. Doctors prescribed it as a sedative and sleeping drug for pregnant women. There is one chiral carbon in the thalidomide molecule. The drug was made and marketed as a racemic mixture of the (+)(R)-thalidomide and (-)(S)-thalidomide.

O O H H O N O N * * N N O O O H H O (-)(S)-thalidomide (+)(R)-thalidomide Tragically, thalidomide was found to have serious side-effects; thousands of babies were born with missing or abnormal arms, hands, legs, or feet. It was banned by many countries in 1961.

Now scientists know that it is the (-)(S)-thalidomide that caused the severe side-effects.

Photos of malformations caused by thalidomide are available at http://www.chm.bris.ac.uk/ motm/thalidomide/first.html.

The action of drugs is usually explained using the receptor theory. Receptors are protein molecules in our body. Because protein molecules are chiral, they have different reaction with the two enantiomers of a chiral drug. In the 1950s, pharmacists and doctors did not know that 2 the (+)(R)-thalidomide is an effective sedative, whereas the (-)(S)-thalidomide is a teratogen (a substance affecting the development of the foetus and causing structural or functional disability). Therefore, the enantiomeric composition of a chiral drug is a critically important issue in drug development. The thalidomide tragedy forced drug companies to reconsider enantiomers as separate molecules rather than just different forms of the same drug.

Not all drug molecules are chiral. Chiral drugs that are produced by chemical synthesis are usually a racemic mixture. Currently, regulatory guidelines do not prohibit the development of racemates of chiral drugs. However, drug companies should investigate the properties of each enantiomer of a new chiral drug before they introduce it to the market.

Questions

1. Why is thalidomide chiral?

2. Why are drug molecules often chiral in order to have positive effects in humans?

3. What should drug companies consider when they develop and market new chiral drugs?

–  –  –

Thalidomide, C13H10N2O4, was first synthesized by a small drug company, Chemie Grünenthal, in West Germany in 1953. Chemie Grünenthal patented the thalidomide molecule and began searching for a disease that it could cure. It was first recommended for the treatment of epilepsy (a disease of the nervous system causing a person to fall unconscious).

Trials indicated that thalidomide could not prevent convulsions, but epilepsy patients reported experiencing a good sleep.

In 1957, thalidomide was introduced to the West German market and it did not require a doctor’s prescription. Actually, nothing was known about the pharmaceutical effects of thalidomide at the time of its marketing. By 1961 thalidomide was the best-selling sleeping pill in West Germany and the UK. Thalidomide was also found to prevent nausea due to pregnancy. It was promoted by Chemie Grünenthal as a completely safe drug for pregnant women.

In 1960, harmful side effects of thalidomide were reported. Patients’ nerves in their hands and feet deteriorated. Worse still, thalidomide was later found to cause severe birth defects when taken by pregnant women. Babies were born with hands and feet protruding directly from their torsos, a condition known as phocomelia. Others had limbless trunks with toes extending from their hips; others were born with just a head and a torso; still others had abnormal internal organs such as heart and kidney. It is estimated that anywhere from 8,000 to 80,000 deformed babies were born in Europe. Many died at birth due to their defects. In November 1961, thalidomide was withdrawn from the German market. The drug was not banned worldwide until 1962. Photos of malformations caused by thalidomide are available at the





following websites:

http://www.thalidomide.org/default_eng.asp?menyid=9&linkid=43 http://www.thalidomide.ca/en/information/brochure1.html Thalidomide was sold as the racemic mixture of enantiomers. (+)(R)-thalidomide is a sedative, but (-)(S)-thalidomide is a teratogen (i.e., a drug which can harm a foetus in the womb).

(-)(S)-thalidomide inhibits new blood vessel growth. This is detrimental to a foetus because new blood vessels provide a “road map” for the growth of limbs and organs during the development of a foetus.

The mechanism of action of (-)(S)-thalidomide is not fully understood. More than 30 mechanisms have been proposed to explain the teratogenic action of (-)(S)-thalidomide. Some

–  –  –

Thus, (-)(S)-thalidomide is the unwanted enantiomer. You might think that drug companies can simply purify the racemic mixture and give patients only the (+)(R)-thalidomide.

Unfortunately, the answer is not that simple. Human liver contains an enzyme that can convert (+)(R)-thalidomide to (-)(S)-thalidomide. Therefore, even administration of enantiomerically pure (+)(R)-thalidomide results in a racemic mixture.

Questions

1. What are the harmful side effects of the chiral drug Thalidomide?

2. Why can thalidomide cause birth defects?

3. If doctors prescribe the pure (+)(R)-thalidomide only, could the harmful side effects of thalidomide be avoided? Why?

–  –  –

In the 1950s and 1960s, thousands of babies were born without arms and legs in Europe. The tragedy was caused by the side effects of a chiral drug called Thalidomide (C13H10N2O4) synthesized by the drug company Chemie Grünenthal in West Germany. Some babies were

also born blind or deaf. Other harmful side effects of thalidomide include:

Spinal cord defects Absent or abnormal external ears Heart, kidney, and genital abnormalities Abnormal formation of the digestive system

–  –  –

Thalidomide, originally used as a sedative for pregnant women, was banned worldwide by WHO (World Health Organization) in 1962. Now doctors know that the greatest risk of thalidomide-induced birth defects is in the first 1-2 month of pregnancy, before a woman may recognize that she is pregnant. Photos of malformations caused by thalidomide are available at http://news.bbc.co.uk/2/hi/health/202713.stm.

However, the ban of thalidomide was lifted in 1985 by WHO. Between 1969 and 1995, 34 cases of thalidomide-induced birth defects were found in South America. Chemie Grünenthal sold 4,000 pills to Hong Kong during the years 1985 to 1992 with the brand name Poli-Gripan.

In July, 1998, the Food and Drug Administration in the USA approved it for the treatment of erythema nodosum leprosum (ENL, an inflammatory complication of leprosy). The drug does not kill the bacteria that cause leprosy, but it does change the body’s immunological response to those bacteria. Thalidomide can decrease the level of TNF-α (tumour necrosis factor alpha) in ENL patients. TNF-α is responsible for the tissue inflammation in ENL patients. WHO does not recommend the use of thalidomide to treat ENL because there are other drugs that work just as well as thalidomide but do not cause birth defects. However, thalidomide is easy 6 to produce at a very low cost. This is the main reason why it is often used in the treatment of ENL in many countries.

In May, 2006, the US Food and Drug Administration also granted approval for thalidomide in combination with another drug called dexamethasone for the treatment of multiple myeloma (a bone marrow cancer). It was approved under accelerated approval regulations which require further clinical trials to demonstrate thalidomide’s benefit in the treatment of multiple myeloma.

The Chemie Grünenthal patent on thalidomide has expired. Today it is legal for anyone to synthesize thalidomide. In the USA, Celgene Corporation sells thalidomide under the trade name “Thalomid”. Celgene is allowed to market it only under a special restricted distribution program approved by the US Food and Drug Administration. It is called the “System for Thalidomide Education and Prescribing Safety (STEPS).” Only prescribers and pharmacists registered with the STEPS program are allowed to prescribe and dispense Thalomid. Patients must be advised of, agree to, and comply with the requirements of the STEP program to receive Thalomid.

Today, thalidomide is used experimentally in all continents to treat various cancers and inflammatory diseases. They are particularly interested in the following three properties of

thalidomide:

Inhibition of the growth of new blood vessels Activation of human immune system Anti-inflammatory effects For example, some drug manufacturers are conducting trials to see if thalidomide can cure breast, prostate, brain, lung and pancreatic cancer. Because thalidomide can inhibit new blood vessels forming in and around tumors, doctors hope that the drug can kill tumors directly by shutting down the blood supply to them. Also, thalidomide is being investigated as a treatment for AIDS (acquired immune deficiency syndrome). More than a million people a year die from AIDS as a result of infection with HIV (human immunodeficiency virus). Some AIDS sufferers cannot eat due to painful ulcers in the mouth and esophagus. Clinical trials indicated that thalidomide may help AIDS patients by reducing their ulcers.

However, thalidomide victims are very concerned about the return of this drug. One of the reasons is that the control of the intake of thalidomide during early pregnancy is very difficult because most pregnancies are unintended. Taking even one thalidomide pill (e.g., one capsule

–  –  –

Thalidomide victims hope that pharmaceutical companies could discover an analogue with the positive clinical effects of thalidomide but without its harmful side effects. One class of thalidomide analogues is called immunomodulatory drugs. Examples are lenalidomide and CC-4047.

–  –  –

In 1999, scientists found that lenalidomide and CC-4047 can inhibit TNF-α and are 2,000 and 20,000 times more potent than thalidomide respectively. Lenalidomide and CC-4047 also stimulate T cells, which are a type of white blood cell involved in a variety of immune reactions. In 2000, analogues of thalidomide were found to have the ability to kill multiple myeloma cells.

Questions

1. Why was thalidomide banned in 1962?

2. Why did the US Food and Drug Administration approve the use of thalidomide in 1998?

3. Thalidomide victims have expressed a lot of concerns about the return of thalidomide to the market. What are their major concerns? What are their recommendations?

8



Similar works:

«Margaret R. Basom & Diane M. Yerkes Educational Leadership and Administration A School-University Partnership in Administrator Preparation: Learnings and Subsequent Questions Margaret R. Basom San Diego State University & Diane M. Yerkes University of San Diego Abstract: School university partnerships have become important in the reform efforts to develop the next generation of school leaders. This study examines one university’s approach of working with several school districts as partners...»

«Targeting and Tailoring an Intervention for Adolescents with Overweight: Some Ethical Concerns Kirsti Riiser Institute of Nursing, Faculty of Health, Oslo and Akershus University College of Applied Sciences, Oslo, Norway; Department of Coaching and Psychology, Norwegian School of Sport Sciences, Oslo, Norway Knut Løndal Department of Primary and Secondary Teacher Education, Faculty of Education and International Studies, Oslo and Akershus University College of Applied Sciences, Oslo, Norway...»

«Last Updated: August 2016 Smiles for Life: A National Oral Health Curriculum The Society of Teachers of Family Medicine (STFM) Group on Oral HealthThird Edition Examination Items Note: Answers to items appear on page 20. Module 1: The Relationship of Oral to Systemic Health 1. What is the most common chronic disease of childhood? A. Asthma B. Seasonal allergies C. Dental caries D. Otitis media 2. The Patient Centered Medical Home is the ideal place for all of the following EXCEPT: A....»

«EPIPHANIES IN ACADEME or MEDITATIONS ON A FLAT CAT Francis Edward Abernethy 2006 Regents Lecture — University Lecture Series Wednesday Feb 8, 2006, at 11 a.m. in the Cole Auditorium Stephen F. Austin State University Myself when young did eagerly frequent Doctor and Saint, and heard great argument About it and about; but evermore Came out by the same door where in I went. Omar Khayyam I came back from The War in 1946 and went to Stephen F. Austin State Teachers College on the GI Bill of...»

«PUBLISHED VERSION Michael Colbung Indigenisation of the curriculum Australian Association of Mathematics Teachers Conference, 2015 / pp.1-6 © 2015 The Authors. PERMISSIONS As per email correspondence from publisher: 9/12/2015 21st December 2015 http://hdl.handle.net/2440/95556 Aboriginalisation of the Australian Curriculum: A focus on Mathematics and Science in South Australia Michael Colbung Introduction Australian curriculum has struggled for many years with the “finding of place” for...»

«File: Sterio 2 Created on: 6/17/2012 6:54:00 PM Last Printed: 9/1/2012 5:02:00 PM KATYN FOREST MASSACRE: OF GENOCIDE, STATE LIES, AND SECRECY Milena Sterio* The Soviet secret police murdered thousands of Poles near the Katyn Forest, just outside the Russian city of Smolensk, in the early spring of 1940. The Soviets targeted members of the Polish intelligentsia—military officers, doctors, engineers, police officers, and teachers—which Stalin, the Soviet leader, sought to eradicate...»

«TMME, vol7, nos.2&3, p.295 Vectors in Climbing Anne Birgitte Fyhn1 University of Tromsø, Norway Abstract: In this article, the work on mesospace embodiments of mathematics is further developed by exploring the teaching and learning of vector concepts through climbing activities. The relevance and connection between climbing and vector algebra notions is illustrated via embedded digital videos. Keywords: climbing and mathematics; digital media; egocentric vs allocentric representations;...»

«DOCUMENT RESUME IR 013 405 ED 298 937 AUTHOR Balajthy, Ernest TITLE Recent Trends in Minicomputer-Based Integrated Learning Systems for Reading and Language Arts Instruction. Mar 88 PUB DATE 27p.; Paper presented at the Rutgers UniverSIty NPTE Spring Reading Conference (New Brunswick, NJ, March 1988). Book/Product Reviews (072) Reports Descrirtive PUB TYPE (141) Speeches/Conference Papers (150) EDRS PRICE MF01/PCO2 Plus Postage. Compensatory Education; *Computer Assisted DESCRIPTORS...»

«1 UNIVERSITE D’ANTANANARIVO ECOLE NORMALE SUPERIEURE DEPARTEMENT EDUCATION PHYSIQUE ET SPORTIVE MEMOIRE DE FIN D’ETUDE POUR L’OBTENTION DU CERTIFICAT D’APTITUDE PEDAGOGIQUE DE L’ECOLE NORMALE SUPERIEURE (C.A.P.E.N) ARCHEOLOGIE ET SIGNIFICATIONS FONCTIONNELLES DU PARITAKY DANSE DANS LA REGION SUD OUEST Par : RATSIMBAZAFY Herilantoniaina Encadré par : Messieurs RATSIMBAZAFY Ernest Et RAMPARANY Saraela Date de soutenance : 19 Octobre 2004 2 UNIVERSTIE D’ANTANANARIVO ECOLE NORMALE...»

«Course: International Marketing Instructor: Mahmood Hussain, PhD Understanding Consumer Behavior in the Asia Pacific Market and Developing Appropriate Marketing Strategies. Country: Australia& Hong Kong Group: # 3 Student Name 1 Student Name 2 Student Name 3 Student Name 4 Date: 1 Contents I.Summary of the Project 4 II.Introduction 5 III.Country Profiles—Australia& Hong Kong • Population, age/ gender distribution, literacy rate. 6 • GDP, GDP per capita. 6 • Foreign Trade and...»

«Ana min al yahud I'm one of the Jews By Almog Behar 1. At that time, my tongue twisted around and with the arrival of the month of Tammuz the Arabic accent got stuck in my mouth, deep down in my throat. Just like that, as I was walking down the street, the Arabic accent of Grandfather Anwar of blessed memory came back to me and no matter how hard I tried to extricate it from myself and throw it away in one of the public trash cans I could not do it. I tried and tried to soften the glottal...»

«Enabling Dance: Dance Education in Australian Schools – practice, pedagogy and quality PD Presentation at DEAS by Dr Katrina Rank, Education & Training Manager, Ausdance Victoria 14 April 2011 I’d like to acknowledge the traditional owners of the land on which we stand and to you for having me here today. I’m going to start with a story (first recounted by arts in education advocate, Sir Ken Robinson). There was once a little girl. She was 8 years old and disruptive in class. She...»





 
<<  HOME   |    CONTACTS
2016 www.dissertation.xlibx.info - Dissertations, online materials

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.